Pancreatic cancer is the fourth leading cause of cancer death among adults in the United State. The mortalityrate of pancreatic cancer is the worst of any malignancies followed in the S.E.E.R. database. Discovery of new therapeutics is critically important for the prevention and treatment of pancreatic cancer. Targeted drug development approaches focus on gain-of-function mutations in oncogenes have led to new treatments for many tumor types, however,the majority of the genetic alterations identified in pancreatic cancer are loss-of-function events, which are not suitablefor targeted drug development and have not been explored so far for drug development due to the difficulties to design small molecule therapies to restore the function of loss-of-function genes. In this proposal, we describe a new strategy that allows us to take advantage of loss-of-function mutations present in pancreatic cancer cells and identify genotype- selective antitumor compounds to kill pancreatic cancers with specific loss-of-function mutations or the most common combination of genetic alterations that have been shown to play a role in the tumorigenesis and progression of pancreatic cancer. The specific aims of this proposal are to: 1. Identify genotype-selective compoundsthat kill pancreatic cancer cells with loss-of-function mutations in specific tumor suppressor genes. 2. Identify a series of genotype-selective compounds that kill pancreatic cancer cells with the most common combination of genetic alterations. 3. Take the compounds discovered in the first two specific aims into clinical trials as rapidly as possible.